Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)

Stable Identifier
R-HSA-9976102
DOI
10.3180/R-HSA-9976102.1
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Pathway
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Homo sapiens
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5/5
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Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)
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Naive (unexposed to antigen) CD4+ T cells are induced to differentiate into T helper 2 cells (Th2 cells) by encounters with dendritic cells presenting antigen peptides on MHC II complexes (reviewed in León 2023). Antigen peptides activate signaling by the T cell receptor (TCR) which is amplified by the interaction between CD80 or CD86 on the dendritic cell and CD28 on the T cell (reviewed in León 2023). Dendritic cells also secrete cytokines that determine the differentiation of CD4+ T cells into various helper and regulatory subtypes, a process called polarization.
The specific cytokine secreted by dendritic cells to initiate Th2 differentiation is not conclusively known but may be Interleukin-2 (IL2) (Granucci et al. 2001, 2003). IL2 from either dendritic cells or T cells activates signaling in the T cell that yields phosphorylated STAT5 dimers. The STAT5 dimers bind and activate the gene encoding IL4R (Liao et al. 2008), a receptor subunit for IL4, and cause opening of chromatin at the IL4 locus (Cote-Sierra et al. 2004). IL4 signaling in the CD4+ T cell produces phosphorylated STAT6 dimers that bind the gene encoding GATA3 (Onodera et al. 2010, reviewed in Onodera et al. 2018), the master regulator of Th2 differentiation.The STAT6 dimers also bind a locus control region (LCR) in the 3' region of the RAD50 gene (Lee and Rao 2004), which is located in a gene cluster that contains genes encoding the Th2 cytokines IL4, IL5, and IL13, and promote their expression (Lee et al. 2003). Expression of GATA3 is also activated by NFATC2 (NFAT1), from TCR signaling (Scheiman and Avri et al. 2009), and NICD1 and NICD2, from Notch signaling (Amsen et al. 2004, 2007, Fang et al. 2007, reviewed in Nakayama and Yamashita 2008, Zhu et al. 2010).
GATA3 is sufficient to direct Th2 differentiation, including expression of Th2-characteristic cytokines (Ouyang et al. 2000). GATA3 (Kanhere et al. 2012), STAT6 dimers (Lee and Rao 2004), and other factors bind the LCR and recruit chromatin modifiers to open chromatin in the region by acetylating histones (Wurster and Pazin 2008).
Th2 cells are characterized by the expression and secretion of the cytokines IL4, IL5, and IL13, which are encoded by genes located with the LCR in a cluster on human chromosome 5 (chromosome 11 in mice). GATA3, NFATC2 and other factors bind the promoters of the IL4 gene (Zheng and Flavell 1997, Sasaki et al. 2013, Hosokawa et al. 2013, Szabo et al. 1993, Rooney et al. 1995, Takemoto et al. 1997) and IL13 gene (Kishikawa et al. 2001, Yamashita et al. 2002, Yao et al. 2012, Hosokawa et al. 2013, Sasaki et al. 2013) and activate expression. GATA3 binds the IL5 gene and can activate or repress it expression, depending on the binding site (Schwenger et al. 2001, Zhang et al. 1997, Lee et al. 1998, Sasaki et al. 2013).
Literature References
PubMed ID Title Journal Year
15004274 Interleukin 2 plays a central role in Th2 differentiation

Cote-Sierra, J, Foucras, G, Guo, L, Chiodetti, L, Young, HA, Hu-Li, J, Zhu, J, Paul, WE

Proc Natl Acad Sci U S A 2004
11579103 GATA-3 has dual regulatory functions in human interleukin-5 transcription

Schwenger, GT, Fournier, R, Kok, CC, Mordvinov, VA, Yeoman, D, Sanderson, CJ

J Biol Chem 2001
18852284 BRG1-mediated chromatin remodeling regulates differentiation and gene expression of T helper cells

Wurster, AL, Pazin, MJ

Mol Cell Biol 2008
11591766 The cell type-specific expression of the murine IL-13 gene is regulated by GATA-3

Kishikawa, H, Sun, J, Choi, A, Miaw, SC, Ho, IC

J Immunol 2001
22226971 Coordinated regulation of IL-4 and IL-13 expression in human T cells: 3C analysis for DNA looping

Yao, X, Zha, W, Song, W, He, H, Huang, M, Jazrawi, E, Lavender, P, Barnes, PJ, Adcock, IM, Durham, AL

Biochem Biophys Res Commun 2012
9310836 Four P-like elements are required for optimal transcription of the mouse IL-4 gene: involvement of a distinct set of nuclear factor of activated T cells and activator protein-1 family proteins

Takemoto, N, Koyano-Nakagawa, N, Arai, N, Arai, K, Yokota, T

Int Immunol 1997
8336717 Identification of cis-acting regulatory elements controlling interleukin-4 gene expression in T cells: roles for NF-Y and NF-ATc

Szabo, SJ, Gold, JS, Murphy, TL, Murphy, KM

Mol Cell Biol 1993
12205084 Identification of a conserved GATA3 response element upstream proximal from the interleukin-13 gene locus

Yamashita, M, Ukai-Tadenuma, M, Kimura, M, Omori, M, Inami, M, Taniguchi, M, Nakayama, T

J Biol Chem 2002
15507491 Molecular analysis of a locus control region in the T helper 2 cytokine gene cluster: a target for STAT6 but not GATA3

Lee, DU, Rao, A

Proc Natl Acad Sci U S A 2004
37100645 A model of Th2 differentiation based on polarizing cytokine repression

León, B

Trends Immunol 2023
20620946 Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation

Wei, L, Vahedi, G, Sun, HW, Watford, WT, Takatori, H, Ramos, HL, Takahashi, H, Liang, J, Gutierrez-Cruz, G, Zang, C, Peng, W, O'Shea, JJ, Kanno, Y

Immunity 2010
15137944 Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells

Amsen, D, Blander, JM, Lee, GR, Tanigaki, K, Honjo, T, Flavell, RA

Cell 2004
23824597 Genome-Wide Gene Expression Profiling Revealed a Critical Role for GATA3 in the Maintenance of the Th2 Cell Identity

Sasaki, T, Onodera, A, Hosokawa, H, Watanabe, Y, Horiuchi, S, Yamashita, J, Tanaka, H, Ogawa, Y, Suzuki, Y, Nakayama, T

PLoS One 2013
7749982 Coordinate and cooperative roles for NF-AT and AP-1 in the regulation of the murine IL-4 gene

Rooney, JW, Hoey, T, Glimcher, LH

Immunity 1995
9160750 The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells

Zheng, W, Flavell, RA

Cell 1997
20065998 Transcriptional regulation of Th2 cell differentiation

Zhu, J

Immunol Cell Biol 2010
18820682 Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression

Liao, W, Schones, DE, Oh, J, Cui, Y, Cui, K, Roh, TY, Zhao, K, Leonard, WJ

Nat Immunol 2008
23471993 Functionally distinct Gata3/Chd4 complexes coordinately establish T helper 2 (Th2) cell identity

Hosokawa, H, Tanaka, T, Suzuki, Y, Iwamura, C, Ohkubo, S, Endoh, K, Kato, M, Endo, Y, Onodera, A, Tumes, DJ, Kanai, A, Sugano, S, Nakayama, T

Proc Natl Acad Sci U S A 2013
10661403 Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment

Ouyang, W, Löhning, M, Gao, Z, Assenmacher, M, Ranganath, S, Radbruch, A, Murphy, KM

Immunity 2000
12871646 Regulation of the Th2 cytokine locus by a locus control region

Lee, GR, Fields, PE, Griffin, TJ, Flavell, RA

Immunity 2003
9261181 Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene

Zhang, DH, Cohn, L, Ray, P, Bottomly, K, Ray, A

J Biol Chem 1997
9498775 Characterization of cis-regulatory elements and nuclear factors conferring Th2-specific expression of the IL-5 gene: a role for a GATA-binding protein

Lee, HJ, O'Garra, A, Arai, K, Arai, N

J Immunol 1998
12734352 Early IL-2 production by mouse dendritic cells is the result of microbial-induced priming

Granucci, F, Feau, S, Angeli, V, Trottein, F, Ricciardi-Castagnoli, P

J Immunol 2003
18502111 Initiation and maintenance of Th2 cell identity

Nakayama, T, Yamashita, M

Curr Opin Immunol 2008
17658278 Notch directly regulates Gata3 expression during T helper 2 cell differentiation

Fang, TC, Yashiro-Ohtani, Y, Del Bianco, C, Knoblock, DM, Blacklow, SC, Pear, WS

Immunity 2007
20956546 STAT6-mediated displacement of polycomb by trithorax complex establishes long-term maintenance of GATA3 expression in T helper type 2 cells

Onodera, A, Yamashita, M, Endo, Y, Kuwahara, M, Tofukuji, S, Hosokawa, H, Kanai, A, Suzuki, Y, Nakayama, T

J Exp Med 2010
23232398 T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements

Kanhere, A, Hertweck, A, Bhatia, U, Gökmen, MR, Perucha, E, Jackson, I, Lord, GM, Jenner, RG

Nat Commun 2012
11526406 Inducible IL-2 production by dendritic cells revealed by global gene expression analysis

Granucci, F, Vizzardelli, C, Pavelka, N, Feau, S, Persico, M, Virzi, E, Rescigno, M, Moro, G, Ricciardi-Castagnoli, P

Nat Immunol 2001
30619290 Epigenetic and Transcriptional Regulation in the Induction, Maintenance, Heterogeneity, and Recall-Response of Effector and Memory Th2 Cells

Onodera, A, Kokubo, K, Nakayama, T

Front Immunol 2018
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Authored
May, B  (2025-12-08)
Reviewed
Barbutti, I  (2026-02-24)
Lord, GM  (2026-02-26)
Created
May, B  (2025-12-08)
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